Upper GI 2017

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

- Radiation Oncologists Vincenzo Valentini (IT) Marcel Verheij (NL) Oscar Matzinger (CH)

- Surgeon, William Allum (UK)

- Medical oncologist Florian Lordick (DE) Nicola Silvestris (IT) - Radiologist Angela Riddell (UK) Riccardo Manfredi (IT)

- Physicist,

Dirk Verellen (BE)

- RTT Lisa Wiersema (NL)

- Delineation Administrator Francesco Cellini, RO (IT)

- Pathologist Alexander Quaas (DE)

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

Clinical cases

Esophageal

Mid third GEJ

•

• Gastric

Partial gastrectomy Total gastrectomy

•

•

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

V.VALENTINI

WELCOME AND INTRODUCTION

47 participants

2

1

Australia

1

Republic of Korea

1

4 1

2

1

72

South Africa

6

3

1 1 1 2

India

1

1

3 5

New Zeland

1

V.VALENTINI

Imaging based staging and response evaluation in Esophageal Cancer

Dr Angela M Riddell Royal Marsden, London. UK

25/03/2017

Esophageal Cancer - Current Staging Strategy

• Diagnosis – Endoscopic biopsy • Initial Imaging:  MDCT

Potentially curable disease: •  PET/CT – exclude distant spread  Laparoscopy  EUS – Early disease, Proximal/ Distal Extent

T staging - MDCT

Initial Staging • T stage - based on wall thickness and outline •Limited soft tissue contrast •Poor for early tumours

pT2

pT3

T Stage Wall thickness Wall Contour

T2

>3mm, <5mm Smooth

T3

5-15mm

Irregular

pT4

T4

>15mm

Contact with adjacent structure

T Staging Accuracy - 74%*

* Davies, A. R., D. A. Deans, et al. (2006). Dis Esophagus 19 (6): 496-503

T staging - MDCT

2016 – 62 patients; Underwent primary surgery

Stage

Sensitivity

Specificity

Accuracy

T2 T3

61% 67%

68% 56%

66% 63%

Sultan R, Haider Z, Chawla TU et al. J Pak Med Assoc. 2016 Jan;66(1):90-2.

N Staging - MDCT

•CT - high specificity, but low sensitivity •Based on size criteria (short axis): ≥6mm perigastric ≥ 8mm extra perigastric ≥10mm mediastinum

No of Regional Nodes

Accuracy of N staging Oesophageal Cancer

Stage

68%*

N1 N2 N3

≤2

3-6

67% †

Gastric Cancer

≥7

* Davies, A. R., D. A. Deans, et al. (2006). Dis Esophagus 19 (6): 496-503 †Hur, J., M. S. Park, et al. (2006). J Comput Assist Tomogr 30 (3): 372-7.

N staging - MDCT

2016 – 62 patients; Underwent primary surgery

Histopathology

CT

Total

Node -ve Node +ve

Node -ve Node +ve

15 17 32

5

20 42 62

25 30

Stage

Sensitivity

Specificity

Accuracy

N Stage

59%

75%

65%

Sultan R, Haider Z, Chawla TU et al. J Pak Med Assoc. 2016 Jan;66(1):90-2.

N Staging - MDCT

Tumour volume related to nodal burden*

*Li, R., T. W. Chen, et al. (2013) Radiology 269 (1): 130-138.

MDCT – M staging

• Detection of hepatic mets: • sens 88%, spec 99%*. • Detection of peritoneal disease • No ascites: sens 30% † • In presence of ascites: • Sens 51%, Spec 97%* • Laparoscopy for potentially operable patients

* Yajima, K., T. Kanda, et al. (2006). Am J Surg 192 (2): 185-90. †D'Elia, F., A. Zingarelli, et al. (2000). Eur Radiol 10 (12): 1877-85.

18 FDG-PET/CT – Staging

Importance of the number of nodes in prognosis

• No of PET-positive nodes before & after chemotherapy associated with survival*

p <0.001

*Miyat H, Yamasaki M, Makino T et al. 2015. BJS Oct 27. doi: 10.1002/bjs.9965. [Epub ahead of print]

18 FDG-PET/CT – Staging

Detection of occult metastases • Initial studies using FDG PET: • Metastatic disease detected in 15% patients considered potentially operable*.

• Prospective trial 187 patients showed confirmed up-staging in 9(4.8%) patients & 18 (9.5%) patients with unconfirmed metastases ‡ • 25/156 ( 16% ) patients up staged to M1b disease on PET- CT §

• False positive results on PET-CT ‡¥ *Flamen, P., A. Lerut, et al. (2000). J Clin Oncol 18 (18): 3202 -10

‡ Meyers, B. F., R. J. Downey, et al. (2007). J Thorac Cardiovasc Surg 133 (3): 738 -45 § Purandare, N. C., C. S. Pramesh, et al. (2014). Nucl Med Commun 35 (8): 864-869 ¥ Adams, H. L. and S. S. Jaunoo (2014). Ann R Coll Surg Engl 96 (3): 207-210

T staging - Endoscopic Ultrasound (EUS)

• Endoscopic Ultrasound is able to delineate the layers of the oesophageal wall • More accurate staging of tumours confined within the wall (

pT1 tumour Courtesy of Dr Martin Benson

Endoscopic Ultrasound – T & N Staging

Multi centre analysis* • High frequency EUS (miniprobe) • Pre therapeutic uT and uN compared to pT/pN classification obtained from esophagectomy (n = 93) or EMR (n = 50)

• Accuracy

• T staging 60% & N Staging 74% • 78% stratified to appropriate therapeutic regime • 11% over-treatment & 11% under-treatment

*Meister, T., H. S. Heinzow, et al. (2013). Surg Endosc 27 (8): 2813-2819

Endoscopic Ultrasound – T & N Staging

• Limitation: stenotic tumours • These tumours are likely to be locally advanced* • Such patients should be offered neoadjuvant

therapy

* Worrell, S. G., D. S. Oh, et al. (2014). J Gastrointest Surg 18 (2): 318-320.

Response to chemotherapy / CRT

Methods used for assessing response: • MDCT: Response Evaluation Criteria in Solid Tumours (RECIST) 18 FDG-PET/CT: Standardised Uptake Value (SUV mean / max) Metabolic tumour volume (MTV) Total lesion glycolysis (TLG) MRI: Apparent Diffusion Coefficient (ADC)

Response to chemotherapy / CRT

Predict outcome for OG patients • responders to neoadjuvant therapy benefit most post surgery • non-responders to neoadjuvant therapy have a poorer prognosis post op than those who have primary surgery alone* β • Individualise patient care

*Ancona E, Ruol A et al. 2001. Cancer; 91:2165-2174 β Law S, Fok M et al 1997. J Thorac Cardiovasc Surg; 14: 210-217

Response to chemotherapy / CRT

Multidetector Computed Tomography (MDCT)

Sept 2012

Dec 2012

3 cycles chemo

Response by RECIST

Response to chemotherapy / CRT

MDCT – measurement of lymph node size &/or metastases offer more consistent measures of response by RECIST

Response to chemotherapy / CRT

Challenges for MDCT • Differences in luminal distension • Lack of soft tissue contrast • Unable to differentiate fibrosis & tumour Detection of response by CT: Sensitivity: 27 – 55%; Specificity: 50 – 91%* Ψ

*Cerfolio RJ, Bryant AS, Ohja B et al 2005. J Thorac Cardiovasc Surg; 129:1232-1241 Ψ Swisher SG, Maish M, Erasmus JJ et al 2004. Ann Thorac Surg; 78: 1152 - 1160

MDCT - Restaging after neoadjuvant chemotherapy

• Predicted T stage correctly in 34 % (12/35) • Overstaged 49 % (17/35) • Understaged 17 % (6/35)*

Accurate N stage was noted in 69 % (24/35) •

• Assessment of oesophageal tumour response should focus on combined morphologic and metabolic imaging

*Konieczny, A., P. Meyer, et al. (2013). Eur Radiol 23(9): 2492-2502.

Response to chemotherapy / CRT

CT Textural analysis §

Kaplan-Meier survival analysis stratified by the uniformity of distribution of grey levels

ROI placed round the tumour

Post treatment uniformity of 0.007 or higher is a positive prognostic indicator (median survival 33.2 months vs 11.7 months) §

§ Yip C, Landau B et al 2014. Radiology 270;1: 141-148

18 FDG-PET/CT - Response to chemotherapy / CRT

• Metabolic response occurs early • Studies (eg MUNICON*) have used a reduction in the standardised uptake value (SUV) at 14 days

• SUV max

reduction of 35-60% have been shown to

correlate with pathological response §

*Lordick F, Ott K et al. 2007 Lancet Oncol 8;9:797-805 § Bruzzi J, Munden R et al. 2007. Radiographics 27;1635 - 1652

18 FDG-PET/CT - Response to chemotherapy / CRT

18 FDG-PET/CT Meta analysis >1500 patients* • Conclusion: metabolic response on 18 FDG-PET is a significant predictor of long-term survival data

*Schollaert, P., R. Crott, et al. (2014). J Gastrointest Surg 18(5): 894-905

Response to chemotherapy / CRT

Challenges for PET-CT • False-positive interpretations • Post radiation therapy (due to

inflammation/ulceration) – after 14/7 treatment • Change related to mucosal biopsy • Radiation damage to surrounding organs (eg liver)

Response to chemotherapy / CRT

Example of false positive PET-CT – area of increased FDG avidity in liver represents radiation induced necrosis/inflammation

Taken from: Bruzzi J, Munden R et al. 2007. Radiographics 27;1635 - 1652

Response to chemotherapy / CRT

Current status for PET-CT Recognised that PET SUV max

does not account for

tumour heterogeneity • Alternatives: • Metabolic Tumour Volume (MTV) • Volume of tumour above a threshold of SUV max • Total Lesion Glycolysis (TLG) • MTV x SUV mean

Response to chemotherapy / CRT

PET/CT images shown with delineation of MTV the SUV threshold of 40% SUV max (Blue) and 25% SUV max (red)

Tamandl D, Gore RM, Fueger B et al. 2015 Eur Radiol Jun 5 [Epub ahead of print]

Response to chemotherapy / CRT

MTVratio & TLGratio shown to be independent predictors of OS following neoadjuvant chemoradiotherapy*

Patients with a decrease in MTV of >50% or a decrease in TLG of >60% were shown to have superior overall survival

*Tamandl D, Gore RM, Fueger B et al. 2015 Eur Radiol Jun 5 [Epub ahead of print]

Response to chemotherapy / CRT

Current status for PET-CT • Useful for response assessment, but consensus required for • timing of scan • optimised parameter to use to measure response (SUV max , SUV mean or MTV) • % change in the parameter that equates to response

Response to chemotherapy / CRT

Response assessment with Diffusion weighted MRI

Ax T2

DWI

ADC

De Cobelli F, Giganti F et al 2013. Eur Radiol 23;2165-2174

Response to chemotherapy / CRT

Responders • Lower pre treatment ADC • Higher post treatment ADC • Change in ADC was inversely proportional to the

pathology tumour regression grade

De Cobelli F, Giganti F et al 2013. Eur Radiol 23;2165-2174

ADC as a prognostic biomarker

Limited small group studies • Baseline ADC values ≤1.4 x10 -3 mm 2 /s were associated with poor prognosis

• ADC value correlated with tumour T stage δ

• Both for patients undergoing surgery alone & following neoadjuvant therapy*

*Giganti F, Salerno A, Ambrosi A et al. 2015 Radiol Med Sep 21 [Epub ahead of print] δ Aoyagi T, Shuto K, Okazumi S et al. 2011 Dig Surg;28(4):252-7

Response to chemotherapy / CRT

EUS – assessment of treatment response •50% reduction in cross-sectional area or tumour thickness* β : • response to treatment • improved survival

*Willis J, Cooper GS et al 2002. Gastrointest Endosc 55;655-661 β Ota M, Murata Y et al 2005. Dig Endosc 17; 59-63

EUS - Reassessment after neoadjuvant chemotherapy (NAC)

Challenges for EUS post neoadjuvant therapy • Unable to differentiate fibrosis / inflammation from tumour (resulting in over-staging) • Unable to detect microscopic of viable tumour (resulting in under-staging) • T staging accuracy 29% • Overstaged 23/45 (51%) • Understaged 7/45 (16%) • N staging accuracy 62% • Conclusion: EUS is an unreliable tool for staging esophageal cancer after NAC*

*Heinzow, H. S., H. Seifert, et al. (2013). J Gastrointest Surg 17 (6): 1050-1057.

Summary

Initial Staging • MDCT • 18 FDG-PET/CT • EUS (early tumours) Provide • TNM staging • prognostic information Individualise Patient care

Summary

Response Assessment MDCT • RECIST – relies on alteration in size; assumes reduction equates to response PET-CT • Useful for early response assessment • Consensus required on technique & values used for response (SUV max ; MTV; TLG) DW-MRI • Potential to quantify response – further validation required to determine utility of ADC as a predictive biomarker

Thank you

3/28/2017

TheRoyalMarsden

2

State of Art of Surgery in a Combined Treatment Perspective: Oesophageal Cancer

William Allum

3

4

LEFT

RIGHT

ANTERIOR

TheRoyalMarsden

EMR vs ESD

ENDOSCOPIC RESECTION

T1a

•

EMR

ESD

pT1 sm1 <500 micro mm

•

– Polypectomy

– En bloc

• well / moderately well differentiated adenocarcinoma

– Piecemeal

– Complications

no lymphatic or venous invasion

•

• intramucosal cancer regardless of size without ulceration

• minute submucosal penetration (sm1) and <20mm

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Endoscopic Resection vs Surgery

Depth of invasion & nodal status

pT1m(1-3)OesophagealACA

ERplus APC

76 38

T Stage (n= 369)

N0

N1

Oesophagectomy

Majorcomplications ER

T1a

147

2 (1.3%)

0%

Surgery

32%

T1b

167

53 (24 %)

90day mortality ER

0%

Total

314

55 (15%)

Surgery

2.6%

4year followup

ER 1patient localrecurrence;4 metachronousneoplasia

– ClarkGWB. OesophagogastricSurgery,GriffinSM&RaimesSA (ed); 1997:p108

Pechetal2001AnnSurg 254:67

9

10

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Aim of Resection

Aim of Resection

Complete resection of primary tumour (R0)

Complete resection of primary tumour (R0)

Clear margins

Clear margins

Lymphadenectomy (>15 nodes)

Lymphadenectomy (>15 nodes)

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Dutch Trial Trans Hiatal Oesophagectomy vs Trans Thoracic Oesophagectomy

5 YEAR SURVIVAL

TTO 39% (CI 30 – 48%)

THO 29% (CI 20 – 38%)

220 patients with mid and lower oesophageal ACA

THO

Lower morbidity

TTO

More nodes More respiratory complications

Hulscher et lN Engl J Med 2002;347:1662-9.

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CROSS Trial 13

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Minimally Invasive Oesophagectomy

101 open; 65 MIO; 9 Conversion

pT1a & pT1b. N0

Intraoperative Morbidity MediumTerm

MIO

Less blood loss

Gastroparesis

Less pain

OPEN

Shorter time

Respiratory

More fatigued

Nafteux et al 2011 Eur J Cardio Surgery 40: 1455

Chemoradiation / Surgery vs Chemoradiation FFCD12 16

15

NutritionalaspectsofEnhancedRecovery

Minimally Invasive Oesophageal Resection

MIRO

TIME

Survival ITT

No. Morbid. 30day mort. HMIO 103 35.9% 17.7% 4.9% Pulm Compl

No.

Pulm Compl

InHosp Mort.

MIO

59

12%

3%

TTO 104 64.4% 30.1% 4.9%

TTO

56

34%

2%

Survival per protocol

Marietteetal2015 JClinOnc33: suppl3: abstr5

Biereetal2012 LancetOnc;379:1887

Bedenne etal2007 JClinOncol25:1160

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Salvage Oesophagectomy

Salvage Surgery after Definitive Chemoradiotherapy for SCC

Persistent disease - 234

Recurrent disease - 74

PERS – Persistent

Anastomotic leak – 17.2%

REC - Recurrent

Surgical site infection – 18.5%

Pulmonary complications – 42.9%

Markaret al 2015; J Clin Onc 33: 3866

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EGJ tumor (TNM 7 th ed.) Oesophagus (ICD-O C15) Includes Oesophagogastric junction (C16.0)

OESOPHAGO-GASTRIC JUNCTIONALADENOCARCINOMA

5 cm

Rules for Classification

• A tumour the epicenter of which is within 5 cm of the oesophagogastric junction and also extends into the oesophagus is classified and staged using the oesophageal scheme. • Tumours with an epicenter in the stomach greater than 5 cm from the oesophagogastric junction or those within 5 cm of the oesophagogastric junction without extension in the oesophagus are classified and staged using the gastric carcinoma scheme.

SIEWERT AEG-Classification

EORTC Consensus St Gallen 2012

Type I Adeno-Ca. Dist. Esoph. Type II True Cardia-Ca. Type III Subcardial Ca.

– Type I – Oesophago-gastrectomy

– Type II – Oesophago-gastrectomy or – Extended Total Gastrectomy

– Type I & II – Mediastinal Lymphadenectomy – 2 field

Focused on tumor-centre location

5 cm 5 cm

– Type III - Extended Total Gastrectomy

R.Siewert, Brit.J.Surg. 1998

Lutzetal Eur J Cancer 2012; 48: 2941-53

23

surgicalauditgroup,January2011

24

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Type II Definition

Survival in Type II according to surgery

Centre of tumour 2cm above or below gastro-oesophageal junction

Defining the centre is NOT easy endoscopy imaging

Decisions based only on the centre ? Too simplistic

Siewert et alAnn Surg 2002; 232: 353-61

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26

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surgicalauditgroup,January2011

TheRoyalMarsden

surgicalauditgroup,January2011

Type II French experience

Type II French experience – Anastomotic leak

Overall (all OGJ cancer)

9%

500 cases (42% all EGJ cancers)

Thoracic

10%

Oesophagogastrectomy

292 (58%)

Abdominal

6%

Extended total gastrectomy

203 (40%)

Thoracic oesophago-jejunal

14%

Other

5 (1%)

Sauvanet et al J Am Coll Surg 2005; 201: 253-62

Sauvanet et al J Am Coll Surg 2005; 201: 253-62

28

27

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Aim of Resection

Proximal Margin according to surgery

Complete resection of primary tumour (R0)

Total Gastrectomy (n= 77)

2.0cm (0.1 – 6.5cm)

Clear margins

Oesophago- gastrectomy (n=199)

5.5cm (0.3 – 16.0cm)

Lymphadenectomy (>15 nodes)

Barbour et al Ann Surg 2007; 246: 1-8

29

TheRoyalMarsden Circumferential resection margin (CRM) size correlates with overall survival Prospective database, single institution study, N = 229

Survival according to cephalad margin

Median Survival (95% CI)

CRM n

Positive 45 1.2 yrs (0.9-1.4) <1mm 48 1.9 yrs (1.4-3.2) 3.5 yrs (2.0–no upper CI) ≥ 2.0mm 105 Not reached 1.0-1.9mm 31

Kaplan-Meier curves of OS by margin size:

--->2.0mm ---1.0-1.9mm ---<1mm ---0mm

Probabilityof survival

Time (years)

 CRM size is a significant prognostic factor for overall survival  40.6% of patients in this study had a CRM <1mm  Post operative chemoradiation did not alter survival in patients with CRM <1mm  BUT smaller CRM may just reflect a larger tumour

Barbour et al Ann Surg 2007; 246: 1-8

Landauetal.,ESMO 2010 (Abstract 711PD)

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NutritionalaspectsofEnhancedRecovery

Survival by CRM

CRM in Neoadjuvant Trials

CS

S

CF ECX CXRT S

OEO2 25% 28% OEO5

41% 33%

CROSS

8% 30%

Radical Surgery – 13% - 2/62

O’Neill et al. BJS 2013; 100:1055-63

TheRoyalMarsden

Positive margin vs negative margin

Survival after Treatment for CRM+

Pre-op Staging

Margin positive

Margin negative

T3N0 T3N1 T3N2

10% 40% 50%

T3N0 nor T1-2N0/1 40%

50% 10%

Median no +LN Mean No +LN

5

0

6.3

1.6

O’Neill et al. BJS 2013; 100:1055-63

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Aim of Resection

Survival by Number examined in N0 Disease Bollschweiller et al 2006

Complete resection of primary tumour (R0)

Clear margins

Lymphadenectomy (>15 nodes)

Bollschweiler et al 2006

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Survival by Nodal Volume

Bollschweiler et al 2006

Lymphadenectomy Common to Both Surgical Approaches

Difference in Lymphadenectomy

Oesophago-Gastrectomy

& Total Gastrectomy

Oesophago-Gastrectomy – Para- oesophageal – Para-aortic/ thoracicduct – Carinal – Bronchial – Paratracheal

Total Gastrectomy – Splenic hilum – Distal splenic – Right gastroepiploic

– Right paracardial – Left paracardial

– Infra-pyloric – Supra-pyloric – Properhepatic artery

– Lesser curve – Left gastric – Coeliac

– Proximal splenic – Common hepatic – Lowest paraoesophageal

3 Field Lymphadenectomy

Risk of Systemic Disease and Number of Nodes Involved Peyre et al 2008

Lerut et al 2004. Ann Surg 240: 962-72

Peyre et al 2008 Ann Surg 248: 979-985

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Thank you for your attention

EGJ tumor (TNM 7 th ed.)

Oesophagus (ICD-O C15) Includes Oesophagogastric junction (C16.0)

Rules for Classification

• A tumour the epicenter of which is within 5 cm of the oesophagogastric junction and also extends into the oesophagus is classified and staged using the oesophageal scheme. • Tumours with an epicenter in the stomach greater than 5 cm from the oesophagogastric junction or those within 5 cm of the oesophagogastric junction without extension in the oesophagus are classified and staged using the gastric carcinoma scheme.

T

N2

47

47

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OEO2 update

OE02 update

Resection Details

– Updated results – Overall survival (from randomisation)

CS

S

Number having surgery Median time to surgery Perioperative deaths

361

386

63 days

16 days

HR (95% CI) = 0.84 (0.72, 0.98) p=0.03

CS

36 (10%)

40 (10%)

S

R0

60%

55%

R1

18%

15%

# at risk

R2

9%

13%

S CS

Inoperable

5%

14%

ASGBI 2008

ASGBI 2008

Surgery

Treatment and Surgery

CF (N=451) ECX (N=446) n % n % P- value 411 91% 387 87% 0.043

897patients

Surgery performed

Yes

CF (451)

ECX(446)

No

40 37

59 44

9%

13%

Reason for no surgery

PD, inoperable, co- morbidity

1cycle (14,3%)

1cycle (12,3%)

2cycles (32,7%)

3cycles (37,8%)

4cycles (363,81%)

2cycles (435,96%)

Allpatients (446)

Allpatients (451)

Patient choice

2 1

7 8

Died

Surgery (11,2%)

Surgery (400,89%)

Surgery (411,91%)

Surgery (8,2%)

Surgery (21,5%)

Surgery (27,6%)

Surgery (331,74%)

Surgery (387,87%)

Resection

Yes

387 94% 364 94% 1.000

No

24

23

6%

6%

Of the 798 who had surgery, 47 (24 CF, 23 ECX) had an open and close operation.

Alderson,Cunninghamet al ASCO 2015

Alderson,Cunninghamet al ASCO 2015

Post-op complications

TheRoyalMarsden

OE02 update Trial Design

Complication

CF (N=397)

ECX (N=376)

n

%

n

%

57%

62%

Any complication

225 107

234 126

27%

34%

Respiratory

Resectable carcinoma of the oesophagus

4%

5%

Thrombo-embolic

16 57 44 36 18 12

17 56 45 42 16 15

14%

15%

Infection

11%

12%

Cardiac

9%

11%

Surgery related

RANDOMISE

5%

4%

Haematological

3%

4%

Chylothorax

11%

10%

Anastomotic

44

38

CS Chemotherapy and then surgery

7%

7%

Other

28 34

28 30

S Surgery alone

9%

8%

Required revisional operation Died within 30 days Died within 90 days

2%

2%

8

10 20

4%

5%

17

Alderson,Cunninghamet al ASCO 2015

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2011-2015 update GOJ and oesophageal only 10/62 adenocarcinoma (16%) 8/62 circumferential, 2/62 distal/proximal 1 previously treated on advanced disease protocol + CRT 70% Siewert 1, 30% Siewert 2 (vs 36% Siewert 1 in margin negative) Pre-op CT demonstrated stable disease in 30%, partial response in 70%

Survival by R0 status

3-year survival (95% CI) R0

57% (52%, 61%) 30% (24%, 36%)

Overall post-operative survival (all patients)

R1

1.00

R2

17% (6%, 33%)

0.75

Unavailable

18% (11%, 27%)

HR (R0 vs others)

2.41 (2.02,2.88)

0.50

P-value

<0.001

0.25

Proportion surviving

0.00

0

1

2

3

4

5

6

7

8

Time from surgery (Years)

91 46 21 12 5 3 1 1 0 Unavailable 29 20 6 5 4 2 2 2 1 R2 232 149 89 62 39 22 17 11 4 R1 442 381 279 223 163 122 79 48 20 R0 At risk

Alderson,Cunninghamet al ASCO 2015

OEO2 update

Progression free survival

Pathology of resected specimens

Median PFS (95% CI)

CS

S

CF

1.53 (1.29,2.74)

1.00

CF

ECX

ECX

1.78 (1.61,2.00) 0.86 (0.74,1.01)

Total

342

327

HR

0.75

P-value

0.0580

Node +ve

195 (58%)

216 (68%)

0.50

Lateral resection margin +ve

78 (25%)

83 (28%)

0.25

Proportion progression free

Size < 4cm 184 (58%)

103 (34%)

0.00

0

1

2

3

4

5

6

7

8

Time from randomisation (Years)

446 309 198 149 115 91 70 45 23 ECX 451 292 188 141 103 66 45 20 13 CF At risk

Size 4.1 – 8.0cm 99 (31%)

161 (52%)

Alderson,Cunninghamet al ASCO 2015

Allum et al J Clin Oncol 2009; 27:5062-7

MRC OEO 5 trial design

Nodal Spread

Patients with resectable

CF x2

Surgery

adenocarcinoma of oesophagus or type 1 and 2 oesophagogastric junction

TRIPLET vs. DOUBLET LONGER DURATION

ECX x4

Surgery

• Primary endpoint: overall survival • Final recruitment: 897 patients (this will provide 74% power to detect a 7% improvement in 3 year survival (from 30% to 37%), or 84% power to detect an 8% improvement (to 38%) • Recruitment completed 31 st October 2011

Alderson,Cunninghamet al ASCO 2015

10

3/28/2017

61

TheRoyalMarsden

Pathology

Conclusions

Data

CF

ECX

Important factors

n

% n

% P-value

Mandard TRG

1-3

43

93

<0.001

15%

32%

Longitudinal margin

4-5

244

194

85%

68%

Nodal dissection

total number harvested thoracic and abdominal nodes

Unavailable 99

75

R0 resection

Yes

211

222

0.058

59%

67%

Similar morbidity and mortality

No

144

111

41%

33%

Unavailable 32

29

Selection based on patient factors

• Mandard grade 1 rate was 9 (3%) CF vs 32 (11%) ECX. • A central pathologyreview of all patients is currently ongoing.

Alderson,Cunninghamet al ASCO 2015

TheRoyalMarsden

CROSS Trial

CROSS Trial

Trial Design

Resectable carcinoma of the oesophagus

RANDOMISE

CRT Chemo radiotherapy (Carboplatin, paclitaxel, 41.4 Gy) and surgery

S Surgery alone

Van Hagen et al NEJM 2012;366:2074-84

TheRoyalMarsden

Health Related Quality of Life after Surgery for Junctional Cancer

Overall survival

1.00

Median survival (95% CI) CF 2.02 (1.80,2.38) ECX 2.15 (1.93,2.53) HR 0.92 (0.79,1.08) P-value 0.8582 3-year survival (95% CI) CF 39% (35%, 44%) ECX 42% (37%, 46%)

CF

ECX

63 patients

20 Ext TG 43 TTO

0.75

Better baseline scores for TTO – fitter group

0.50

6/12 HQRL lower scores after TTO Role and Social Function Global Quality of Life Fatigue

0.25

Proportion surviving

0.00

0

1

2

3

4

5

6

7

8

Time from randomisation (Years)

446 343 229 172 124 91 70 45 23 ECX 451 345 227 167 121 71 46 21 13 CF At risk

Barbour et al 2008, BJS 95: 80-4

Alderson,Cunninghamet al ASCO 2015

11

3/28/2017

Overall survival

Dutch Trial THO vs TTO

3-year survival (95% CI) CF 39% (35%, 44%) ECX 42% (37%, 46%) OE02 CS 31% (27%, 36%)

1.00

CF

ECX

OE02CS

– TTO

0.75

– More nodes – More respiratory complications – Lower oesophageal and LN 1-8 better outcome

0.50

0.25

Proportion surviving

0.00

0 1 2 3 4 5 6 7 8 Time from randomisation (Years)

CF At risk

446 343 229 172 124 451 345 227 167 121

70 91 71

50 70 46

38 45 21

27 23 13

ECX

OE02CS

400 235 154 120

85

Alderson,Cunninghamet al ASCO 2015

Survival after TTO vs THO for Type II Tumours

Survival of ALL Px

100

THO 2-Stage RMH

75

50

25

Percent survival

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 0

MedianSurvival

Survival

RMH 54months THO 49months 2ST 34months P< 0.0005

SurvivalofTHOvs2-ST ALLT1-2N+:Survivalproportions

SurvivalofTHOvs 2-ST ALLT1-2N0:Survivalproportions

SurvivalofTHOvs2-ST ALLN1:Survivalproportions

SurvivalofTHOvs2-ST N0:Survivalproportions

100

100

100

THO 2Stage

THO 2Stage

100

THON1 2-STN1

THON0 2-STN0

75

75

75

75

50

50

50

50

25

25

25

Percent survival

25

Percent survival

Percent survival

Percent survival

0 365 730 109514601825 21902555 29203285 3650 0

0 365 730 1095 14601825 2190 2555 2920 3285 3650 0

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 0

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 0

Survival

Survival

Survival

Survival

SurvivalofTHOvs2-ST ALLT3-4N+:Survivalproportions

SurvivalofTHOvs2-ST ALL T3-4N0:Survivalproportions

SurvivalofTHO vs 2-ST ALL N2:Survivalproportions

SurvivalofTHO vs 2-ST ALL N3:Survivalproportions

100

100

THO 2Stage

THO 2Stage

100

100

THON2 2-STN2

THON3 2-STN3

75

75

75

75

50

50

50

50

25

25

Percent survival

Percent survival

0 365 730 109514601825 21902555 29203285 3650 0

25

25

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 0

Percent survival

Percent survival

Survival

Survival

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 0

0 365 730 1095 1460 1825 2190 2555 2920 3285 3650 0

Survival

Survival

P= ns

P= ns

12

3/28/2017

JCOG 9502: Scheme

TheRoyalMarsden

Overall Survival

Gastric carcinoma, esoph. inv. (<3 cm) T2-4,N0-2, M0

1 .0

0 .9

A群 Ｂ群

0 .8

AT: Abdominal (n=82)

Pre-op. Randomization institution,macroscopic type, clinical T

0 .7

0 .6

割 合

0 .5

0 .4

Abdominal (AT) Total gastrectomy, D2 + left upper paraaortic dissection

Thoraco-abdominal (LT) Total gastrectomy, D2 + left upper paraaortic + mediastinal dissection

LT: Thoraco-abd. (n=85)

0 .3

0 .2

Proportion surviving

0 .1

0 .0

0

1

2

3

4

5

6

7

8

9

10

登録後年数 Years after randomization

Observation if curative resection

Sasako M. Lancet Oncol 2006

TheRoyalMarsden

TheRoyalMarsden

Conclusions of JCOG 9502

Health Related Quality of Life after Surgery for Junctional Cancer

63 patients

20 Ext TG 43 TTO

Thoraco-abdominal approach is not recommended for tumors of Siewert’s type 2 and 3.

Better baseline scores for TTO – fitter group

6/12 HQRL lower scores after TTO Role and Social Function Global Quality of Life Fatigue

Barbour et al 2008, BJS 95: 80- 4

TheRoyalMarsden

TheRoyalMarsden

Aim of Surgery for Junctional Cancer

Surgical Options According to Type

Siewert Type I

TTO / THO

R0 resection Minimum 15 lymph nodes 5cm grossly normal in situ proximal oesophagus

Siewert Type II TTO / THO / Ext TG

Siewert Type III Ext TG

13

3/28/2017

TheRoyalMarsden

Resection Margin and Procedure

OPERATIVE MORBIDITY FOR JUNCTIONAL PROCEDURES

171 AEG Patients

SERIES

PROCEDURE

NO.

OPERATIVE MORTALITY

OPERATIVE MORBIDITY

SPECIFIC MORBIDITY

16 Oesophagectomy 71 Left Thoraco-abdominal 84 Transhiatal

Meyer etal (2002)

TTO LTAExt TG

56 74

5.3% 1.4%

41%

Respiratory

Margin: proximal limit of tumour above junction > 5cm – oesophagectomy 3 – 5cm – left thoraco-abdominal < 3cm - Transhiatal

Lerutet al (2004)

TTO 3 field

174

1.2%

58%

Respiratory 32.8% Arrythmia 10.9%

Internulloet al (2008)

LTA

94 (>75yrs)

7.4%

51.9%

Respiratory37%

Ott etal (2009)

TTO

240

3.8%

17.9%

Respiratory

Liet al (2011)

LTA

135

0%

11%

Respiratory6% Leak 1% Wound Infection 4%

Nakamura et al 2008, Hep Gastr 55: 1332-7

Multimodality treatment of oesophageal cancer

Lymphadenectomy in Oesophago-Gastrectomy

Adenocarcinoma

Squamous cell carcinoma

Definitive Chemo- radiation

Pre-operative chemotherapy

Pre-operative chemotherapy

Pre-operative chemotherapy

Pre-operative chemoradiation

Surgery

Surgery

Surgery

Surgery

Post-operative chemotherapy

Frequency of Nodal Involvement Pedrazzani et al 2007

83

Nodal Distribution in Type II

Siewert et al 2002

Pedrazzani et al 2007

14

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85

TheRoyalMarsden

Operation Selection

Pattern of lymph node spread En bloc resection

Surgical Approach Margins Lymphadenectomy

Leers et al. J Thor & Cardio 2009; 138: 594

TheRoyalMarsden

Operation Selection

Pattern of Recurrence of Type I & II Junctional Cancer

Surgical Approach Margins Lymphadenectomy

Wayman et al. Br J Cancer 2002, 86: 1223

TheRoyalMarsden

Lymph Node Spread from Type II

Right Cardiac Lesser Curve Left Cardiac

38.2% 35.1% 23.1% 20.9%

Left Gastric Artery

5 year Survival N0 76.6% N1 62.3% N2 22.4%

Yamashita et al, 2011, Ann Surg 254: 274-80

15

Upper GI: technical and clinical challenges for RO

State of art of radiation therapy

in a combined treatment perspective

Vincenzo Valentini

State of art of radiation therapy in Esophageal Cancer

 Preoperative Chemoradiation  Planned Esophagectomy

 Definitive Chemoradiation  Salvage Esophagectomy

 Chemoradiation  or Selective Esophagectomy

 Preoperative Chemoradiation  Planned Esophagectomy

• Phase III Trials RT( ± CT)  Surg vs Surg alone

 All SCC  RT Doses: 20-40 Gy  pCR ≈ 15%  Local Failure (LF): 20-58%  5 yy SVV: 10-30%

• Lanuois et al ; 1981 • Arnott et al ; 1992

• Wang et al ; 1989 • Gignoux et al ; 1987 • Nygaard et al ; 1992

No Statistical Difference

 Preoperative Chemoradiation  Planned Esophagectomy

 Preoperative Chemoradiation  Planned Esophagectomy • Walsh et al – 1996 (Trimodality)

Phase III Trial Chir ± Preop RTCT Phase III Trial Chir ± Preop RTCT

• CROSS - 2015 (Trimodality) • FFCD 9901 - 2014 (Trimodality) • POET - 2009 (Trimodality) • Urba et al – 2001 (Trimodality) • Burmeister et al – 2005 (Trimodality) • Tepper et al – 2008 (Trimodality)

Phase III Trial Chir ± Preop RTCT

Phase III Trial Chir ± Preop RTCT

Phase III Trial Chir Preop RTCT Phase III Trial Chir ± Preop RTCT ± Phase III Trial Chir + Preop CT ± RT

 Preoperative Chemoradiation  Planned Esophagectomy

• Walsh et al – 1996 (Trimodality)

Stage n.a.

Cardia 36%

113 pts

Adeno 100%

SVV Benefit

RTCT (3DCRT): 40 Gy (2.7 Gy fx) + 5Fu/CDDP EQD2: 42.33 Gy

Walsh et al ; N Engl J Med 1996 (Ireland)

 Preoperative Chemoradiation  Planned Esophagectomy

• Urba et al – 2001 (Trimodality)

Stage: n.a.

Mid-Distal= 92%

100 pts

Adeno 75%

NO SVV Benefit

RTCT (3DCRT): 45 Gy (1.5 Gy fx x 2/day) + 5Fu/CDDP/Vimblastine EQD2: 48.75 Gy

Urba et al ; JCO 2001 (USA)

 Preoperative Chemoradiation  Planned Esophagectomy

• Burmeister et al – 2005 (Trimodality)

Stage: n.a.

Mid-Distal=

79%

256 pts

Adeno 62%

NO SVV Benefit

RTCT (Simulator): 35 Gy (2.4 Gy fx) + 5Fu/CDDP EQD2: 36.17 Gy

Burmeister et al ; Lancet Oncol 2005 (Australia)

 Preoperative Chemoradiation  Planned Esophagectomy

• Tepper et al – 2008 (Trimodality)

Stage n.a.

Low third n.a.

56 pts

Adeno 75%

SVV Benefit

EQD2: 49.56 Gy

RTCT: 50.4 Gy (1.8 Gy fx) + 5Fu/CDDP

Tepper et al ; JCO 2008 (USA)

 Preoperative Chemoradiation  Planned Esophagectomy

• POET - 2009 (Trimodality)

uT3-4NXM0

Siewert I-III= 100%

126 pts (326 planned)

Adeno 100%

NO SVV Benefit

CH + Surg RTCH + Surg

RTCT (Simulator): 2PLF + 30 Gy (2 Gy fx) + CDDP/Etoposide EQD2: 30 Gy

Stahl et al ; JCO – 2009 (Germany)

 Preoperative Chemoradiation  Planned Esophagectomy

• POET - 2009 (Trimodality)

uT3-4NXM0

Siewert I-III= 100%

126 pts (326 planned)

Adeno 100%

NO SVV Benefit  Significant improvement of pCR (2 vs 15.6%; p=0.03) favoring RTCT

 Significant improvement of pN0 (36.7 vs 64.4%; p=0.03) favoring RTCT Stahl et al ; JCO – 2009 (Germany)

 Preoperative Chemoradiation  Planned Esophagectomy

• FFCD 9901 - 2014 (Trimodality)

Stage I-II

Below carina= 91%

194 pts

Adeno 29%

NO SVV Benefit

RTCT: 45 Gy (1.8 Gy fx) + 5FU + Platinum

EQD2: 44.25Gy

Mariette et al ; JCO – 2014 (France)

 Preoperative Chemoradiation  Planned Esophagectomy

• CROSS - 2015 (Trimodality)

T1N1+T2-3N0-1M0

Junction= 24%

366 pts

Adeno 75%

Signif SVV Benefit

RTCT: 41.4 Gy (1.8 Gy fx) + Carbo/Paclitaxel

EQD2: 40.71 Gy

Van Hagen et al ; N Engl J Med 2012 Oppedijk et al; JCO 2014 Shapiro et al ; Lancet Oncol 2015

The Netherlands

 Preoperative Chemoradiation  Planned Esophagectomy

 Preoperative Chemoradiation  Planned Esophagectomy

EQD2

Tumor site

N. Histology

• Walsh et al – 1996

Cardia 36% 113 pts Adeno 100% EQD2: 42.33 Gy

Mid-Distal 92% 100 pts Adeno 75%

EQD2: 48.75 Gy

• Urba et al – 2001

Mid-Distal 79% 256 pts Adeno 62%

• Burmeister et al – 2005

EQD2: 36.17 Gy

EQD2: 49.56 Gy

Low third n.a.

56 pts Adeno 75%

• Tepper et al – 2008

Siewert I-III 100% 126 pts Adeno 100% EQD2: 30 Gy

• POET - 2009

• FFCD 9901 – 2014

Below carina 91% 194 pts Adeno 29%

EQD2: 44.25Gy

Junction 24% 366 pts Adeno 75% EQD2: 40.71 Gy

• CROSS - 2015

Statistically in favour of Preop ChemoRT

Mod from Cellini et al ; Radiat Oncol 2014 (Italy)

 Preoperative Chemoradiation  Planned Esophagectomy

 Preoperative Chemoradiation  Planned Esophagectomy

EQD2

Tumor site

N. Histology

• Walsh et al – 1996

Cardia 36% 113 pts Adeno 100% EQD2: 42.33 Gy

Mid-Distal 92% 100 pts Adeno 75%

EQD2: 48.75 Gy

• Urba et al – 2001

Mid-Distal 79% 256 pts Adeno 62%

• Burmeister et al – 2005

EQD2: 36.17 Gy

EQD2: 49.56 Gy

Low third n.a.

56 pts Adeno 75%

• Tepper et al – 2008

• FFCD 9901 – 2014

Below carina 91% 194 pts Adeno 29%

EQD2: 44.25Gy

Junction 24% 366 pts Adeno 75% EQD2: 40.71 Gy

• CROSS - 2015

Statistically in favour of Preop ChemoRT

Mod from Cellini et al ; Radiat Oncol 2014 (Italy)

 Preoperative Chemoradiation  Planned Esophagectomy

 Preoperative Chemoradiation  Planned Esophagectomy

EQD2

Tumor site

N. Histology

• Walsh et al – 1996

Cardia 36% 113 pts Adeno 100% EQD2: 42.33 Gy

Mid-Distal 92% 100 pts Adeno 75%

EQD2: 48.75 Gy

• Urba et al – 2001

Mid-Distal 79% 256 pts Adeno 62%

• Burmeister et al – 2005

EQD2: 36.17 Gy

EQD2: 49.56 Gy

Low third n.a.

56 pts Adeno 75%

• Tepper et al – 2008

Junction 24% 366 pts Adeno 75% EQD2: 40.71 Gy

• CROSS - 2015

Statistically in favour of Preop ChemoRT

Mod from Cellini et al ; Radiat Oncol 2014 (Italy)

 Preoperative Chemoradiation  Planned Esophagectomy

 Preoperative Chemoradiation  Planned Esophagectomy

EQD2

Tumor site

N. Histology

Mid-Distal 79% 256 pts Adeno 62%

• Burmeister et al – 2005

EQD2: 36.17 Gy

Stage: T1–3, N0–1 M0

Stage: T1N1+T2-3N0-1M0

Junction 24% 366 pts Adeno 75% EQD2: 40.71 Gy

• CROSS - 2015

Statistically in favour of Preop ChemoRT

Mod from Cellini et al ; Radiat Oncol 2014 (Italy)

 Preoperative Chemoradiation  Planned Esophagectomy

• Propensity score match

442 ptz available multi-center (10 Europe)

resectable Esophageal or GEJ Siewert type I and II (stage II or III) , adenocarcinoma 100%

NCR+S (221ptz) = RTCT “CROSS” approach , followed by surgery.

NC+S (221ptz) = CT “MAGIC” approach , including surgery.

Evaluation period 2001-2012; follow-up until 2015

Markar SR et al – Ann Oncol - 2016 (Ireland)

 Preoperative Chemoradiation  Planned Esophagectomy

• Propensity score match

442 ptz available multi-center (10 Europe)

resectable Esophageal or GEJ Siewert type I and II (stage II or III) , adenocarcinoma 100%

• 3-year overall survival 57.9% versus 53.4%;

HR= 0.89, 95%C.I. 0.67-1.17, p = 0.391

• disease-free survival 52.9% versus 48.9%; HR = 0.90, 95%C.I. 0.69-1.18, p = 0.443

Evaluation period 2001-2012; follow-up until 2015

Markar SR et al – Ann Oncol - 2016 (Ireland)

 Preoperative Chemoradiation  Planned Esophagectomy

• Propensity score match

442 ptz available multi-center (10 Europe)

resectable Esophageal or GEJ Siewert type I and II (stage II or III), adenocarcinoma 100%

• ypT0 = NCR+S= 26 .7% versus NC+S= 5%; p <0.001 ; • R1/2 resection margins = NCR+S= 7.7% versus NC+S= 21.8 %; p < 0.001 ;

• ypN 0 = NCR+S= 63 .3% versus NC+S= 32.1%; p < 0.001 ; • lymph node harvest = NCR+S= 14% versus NC+S= 27 %; p < 0.001 ;

• 30+90-day mortality = No sign diffs • anastomotic leak = NCR+S= 2 3. 1% versus NC+S= 6.8 %; p < 0.001 ;

Evaluation period 2001-2012; follow-up until 2015

Markar SR et al – Ann Oncol - 2016 (Ireland)

State of art of radiation therapy in Esophageal Cancer

 Preoperative Chemoradiation  Planned Esophagectomy • Walsh et al – 1996 (Trimodality)

Phase III Trial Chir ± Preop RTCT Phase III Trial Chir ± Preop RTCT

• Urba et al – 2001 (Trimodality) • Burmeister et al – 2005 (Trimodality) • Tepper et al – 2008 (Trimodality)

Phase III Trial Chir ± Preop RTCT

Phase III Trial Chir ± Preop RTCT

• POET - 2009 (Trimodality)

Phase III Trial Chir + Preop CT ± RT

• CROSS - 2015 (Trimodality) • FFCD 9901 - 2014 (Trimodality)

Phase III Trial Chir ± Preop RTCT Phase III Trial Chir ± Preop RTCT

 Definitive Chemoradiation  Salvage Esophagectomy • RTOG 85-01 - 1999

Phase III Trial RT vs RTCT

• INT 0123 - 2002

Phase III Trial RTCT (50Gy) vs RTCT (65Gy)

 Definitive Chemoradiation  Salvage Esophagectomy

• RTOG 85-01 – 1999 • RTOG 85-01 - 1999

Phase III Trial RT (64Gy) vs RTCT (50Gy)

T1-3 N0-1M0

Low third: n.a.

• RTOG 85-01 – 1999

129 pts

Adeno 21.4%

• RTOG 85-01 – 1999

SVV Benefit (RTCT vs RT Alone)

50 Gy- EQD2: 49.17 Gy

• INT 0123 - 2002

Phase III Trial RTCT (50Gy) vs RTCT (65Gy)

• INT 0123 – 2002 • INT 0123 – 2002

T1-T4 N0-1M0

Low third: n.a. Hystotype: n.a.

218 pts

• INT 0123 – 2002

NO SVV Benefit

Cooper et al ; - JAMA – 1999 Minsky et al; JCO 2002

USA

State of art of radiation therapy in Esophageal Cancer

 Preoperative Chemoradiation  Planned Esophagectomy • Walsh et al – 1996 (Trimodality)

Phase III Trial Chir ± Preop RTCT Phase III Trial Chir ± Preop RTCT

• CROSS - 2015 (Trimodality) • FFCD 9901 - 2014 (Trimodality) • POET - 2009 (Trimodality) • Urba et al – 2001 (Trimodality) • Burmeister et al – 2005 (Trimodality) • Tepper et al – 2008 (Trimodality)

Phase III Trial Chir ± Preop RTCT

Phase III Trial Chir ± Preop RTCT

Phase III Trial Chir + Preop CT ± RT Phase III Trial Chir ± Preop RTCT

Phase III Trial Chir ± Preop RTCT

 Definitive Chemoradiation  Salvage Esophagectomy • RTOG 85-01 - 1999

Phase III Trial RT vs RTCT

• INT 0123 - 2002

Phase III Trial RTCT (50Gy) vs RTCT (65Gy)

 Chemoradiation  or Selective Esophagectomy

• FFCD 9102 - 2015 • ESSEN Trial - 2005

Phase II Trial RTCT ± Selective Chir

Phase III Trial RTCT in > PR RTCT vs Selective Chir

 Chemoradiation  or Selective Esophagectomy

• ESSEN Trial – 2005

Low third: 0%

T3-4, N0-1, M0

172 pts

Adeno 0%

EQD2: 40 Gy

EQD2: 50 Gy

EQD2: 60 Gy

Stahl et al ; JCO 2005 (Germany)

 Chemoradiation  or Selective Esophagectomy

• ESSEN Trial – 2005

Low third: 0%

T3-4, N0-1, M0

172 pts

Adeno 0%

Local control

Survival

Surg +

Surg -

Surg +

Surg -

Stahl et al ; JCO 2005 (Germany)